title: Discovery of ligands for a novel target, the human telomerase RNA, based on flexible-target virtual screening and NMR.
abstract: The human ribonucleoprotein telomerase is a validated anticancer drug target, and hTR-P2b is a part of the human telomerase RNA (hTR) essential for its activity. Interesting ligands that bind hTR-P2b were identified by iteratively using a tandem structure-based approach: docking of potential ligands from small databases to hTR-P2b via the program MORDOR, which permits flexibility in both ligand and target, with subsequent NMR screening of high-ranking compounds. A high percentage of the compounds tested experimentally were found via NMR to bind to the U-rich region of hTR-P2b; most have MW < 500 Da and are from different compound classes, and several possess a charge of 0 or +1. Of the 48 ligands identified, 24 exhibit a decided preference to bind hTR-P2b RNA rather than A-site rRNA and 10 do not bind A-site rRNA at all. Binding affinity was measured by monitoring RNA imino proton resonances for some of the compounds that showed hTR binding preference.
authors.affiliation: Department of Pharmaceutical Chemistry, MC 2280, University of Californias San Francisco, 600 16th Street, San Francisco, California 94158-2517, USA.
authors.forename: Irene Gómez
authors.initials: IG
authors.lastname: Pinto
authors.forename: Christophe
authors.initials: C
authors.lastname: Guilbert
authors.forename: Nikolai B
authors.initials: NB
authors.lastname: Ulyanov
authors.forename: Jay
authors.initials: J
authors.lastname: Stearns
authors.forename: Thomas L
authors.initials: TL
authors.lastname: James
mesh_terms: D000634:Aminoquinolines / Q000737:chemistry / Q000494:pharmacology; D003198:Computer Simulation; D016208:Databases, Factual; D055808:Drug Discovery / Q000379:methods*; D006576:Heterocyclic Compounds, 4 or More Rings / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D008970:Molecular Weight; D010640:Phenothiazines / Q000737:chemistry / Q000494:pharmacology; D011084:Polycyclic Aromatic Hydrocarbons / Q000737:chemistry / Q000494:pharmacology; D012313:RNA / Q000737:chemistry* / Q000378:metabolism*; D012015:Reference Standards; D013329:Structure-Activity Relationship; D019098:Telomerase / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D000634:Aminoquinolines; D006576:Heterocyclic Compounds, 4 or More Rings; D008024:Ligands; D010640:Phenothiazines; D011084:Polycyclic Aromatic Hydrocarbons; C422952:telomerase RNA; D012313:RNA; D019098:Telomerase